CXCR4
protein-codingC-X-C motif chemokine receptor 4, the group of CD molecules|C-X-C motif chemokine receptors
Gene summary
This gene encodes a CXC chemokine receptor specific for stromal cell-derived factor-1. The protein has 7 transmembrane regions and is located on the cell surface. It acts with the CD4 protein to support HIV entry into cells and is also highly expressed in breast cancer cells. Mutations in this gene have been associated with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008674
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0023880
Submitter: ClinGen
*CXCR4* was first reported in relation to autosomal dominant WHIM syndrome in 2003 (Hernandez PA, et al., 2003, PMID: 12692554). *CRCX4* is a G-protein–coupled receptor, specific for CXCL12, which initiates signal transduction to activate downstream effectors such as calcium flux, AKT, and Erk1/2 to trigger cellular responses, including adhesion and cell migration. WHIM syndrome has four key manifestations: warts (due to HPV infection), hypogammaglobulinemia, immunodeficiency, and myelokathexis (reviewed in PMID: 30565238). Mature neutrophils fail to exit the bone marrow and B- and T-cell abundance or function is variably deficient. WHIM patients with significant T cell lymphopenia can by identified by TREC-based newborn screening (PMID: 33415666). There are differences in clinical expressivity and all patients may not have the full tetrad of WHIM features (i.e., PMID: 16275383). The mechanism of disease is proposed as gain-of-function; decreased internalization of mutated *CXCR4* leads to prolongation/enhancement of signaling and may provide the biochemical basis for the autosomal dominant abnormalities of cell trafficking and function associated with WHIM syndrome. All reported, genetically defined cases have variants altering the last 10-19 amino acids in the carboxy-tail, with at least ten variants (predominantly nonsense and frameshift) reported. This curation includes ten probands from eight publications (PMIDs: 12692554, 15026312, 17087743, 19321197, 22596258, 23009155, 24139496, 27059040) and 13 additional affected family members. Additional cases are available in the literature (including PMID: 35947323) however the maximum score for genetic evidence has been reached. A role in disease is supported by expression of *CXCR4* in bone marrow and lymphoid tissue (PMID: 9570576) where *CXCR4* functions as a regulator of neutrophil release (PMID: 19264920), which is altered in patients due to impaired internalization (PMID: 15536153). A partial blockade by a *CXCR4* antagonist, rescues the phenotype in patients, including an increase in absolute lymphocyte, monocyte, and neutrophil counts (PMID: 21890643). Additionally, neutropenia and myelokathexis have been recapitulated in mice (PMID: 22438253) and zebrafish (PMID: 20592249) genetically modified to express *CXCR4* variant Arg334Ter. In summary *CXCR4* is definitively associated with autosomal dominant WHIM syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0008674
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:8000006
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:8000006
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Hematologic
Intervention: Allergy/Immunology/Infectious; Hematologic
Rationale: Individuals can be susceptible to a number of types of infections as well as hematologic sequelae, and prophylaxis and medical management (eg, including HPV vaccine, GCSF, CXCR4 antagonists) and early and aggressive treatment of infections can be beneficial
Comments: Because of HPV infections, the condition may include oncologic manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CXCR4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003467.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 62 | 62 | ||||
| missense | 1 | 94 | 22 | 2 | 119 | |
| nonsense | 6 | 2 | 5 | 13 | ||
| start loss | 0 | |||||
| frameshift | 25 | 10 | 3 | 38 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 31 | 13 | 102 | 84 | 2 | 232 |
Highest pathogenic variant AF is 6.8510514e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003458.1 | 2 | MANE Select | |
| Ensembl | ENSP00000241393.3 | 2 | MANE Select | |
| RefSeq | NP_001008540.1 | 1 | Standard | |
| RefSeq | NP_001334985.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cxcr4a | Danio rerio | Structure: endodermal cell Quality: mislocalised anteriorly abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Endocytosis - Homo sapiens (human)
- Chemokine signaling pathway - Homo sapiens (human)
- Axon guidance - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Cytokine-cytokine receptor interaction - Homo sapiens (human)
Biological Process
- activation of MAPK activity
- response to hypoxia
- dendritic cell chemotaxis
- apoptotic process
- chemotaxis
Molecular Function
- virus receptor activity
- actin binding
- G protein-coupled receptor activity
- protein binding
- coreceptor activity
Cellular Component
- cytoplasm
- lysosome
- early endosome
- late endosome
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000409817
- Coding exons
- 1
- Length
- 3817
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.66 | 123 | 187 | 0.658 | 0.0000104 | 2335 |
| Missense (PolyPhen) | 40 | 87.362 | 0.45786 | 1126 | ||
| Synonymous | 1.49 | 62 | 78.9 | 0.786 | 0.00000467 | 725 |
| Loss of Function | 1.48 | 4 | 8.69 | 0.460 | 4.65e-7 | 117 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation (PubMed:10452968, PubMed:28978524, PubMed:18799424). Plays a role in regulation of cell migration, e.g. during wound healing (PubMed:28978524). Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels (PubMed:20228059). Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival (By similarity). {ECO:0000250|UniProtKB:P70658, ECO:0000269|PubMed:10074102, ECO:0000269|PubMed:10452968, ECO:0000269|PubMed:10644702, ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:17197449, ECO:0000269|PubMed:18799424, ECO:0000269|PubMed:20048153, ECO:0000269|PubMed:20228059, ECO:0000269|PubMed:20505072, ECO:0000269|PubMed:28978524, ECO:0000269|PubMed:8752280, ECO:0000269|PubMed:8752281}.;
- Disease
- DISEASE: WHIM syndrome (WHIMS) [MIM:193670]: Immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis. {ECO:0000269|PubMed:12692554}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.792
Intolerance Scores
- LoFtool
- 0.329
- RVIS EVS
- -0.3
- RVIS percentile EVS
- 32.62
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.714
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |